Project 2 will use intemnediate pathologic phenotypes to explore associations with genetic variants in progres- sive supranuclear palsy (PSP) and Lewy body disease (LBD). The results will provide insights into the molecular underpinnings of Parkinsonian disorders. We will use MAPT, as well as non-M(4PT single nucleotide polymor- phisms (SNPs) from genome-wide association studies (GWAS). Aim 1. Generate intermediate pathologic phenotypes for PSP. We will measure burden of tau using digital imaging in superior frontal gyrus, motor cortex, amygdala, caudate nucleus, pontine base and cerebellar dentate nucleus; microgliosis with IBA-1 immunohisto- chemistry in subthalamic nucleus and substantia nigra. We will record clinical phenotypes (sex, diagnosis, age at onset, age at death, disease duration), pathologic groupings (typical PSP vs. atypical PSP; pure PSP vs. mixed PSP), semi-quantitative scores of neuronal, astrocytic and oligodendroglial lesion density, biochemical characte- rization of tau from Western blots of caudate nucleus, and estimated latent trait variables constructed from the semiquantitative lesion scores. Aim 2. Assess association of intermediate pathologic phenotypes with gene variants in PSP. We will focus on 2 AMPT SNPs and 23 non-MAPT SNPs that achieved p<1x10'^ in the PSP GWAS. Each SNP will be tested for association in more than 700 PSP cases against 5 primary pathologic phe- notypes. We hypothesize that intermediate pathologic phenotypes, a large sample size and targeted SNPs will be powerful in identifying mechanisms of genetic risk variants in PSP. Aim 3. Generate intermediate patholog- ic phenotypes for LBD. We will measure burden of a-synuclein, A3, and tau in mid-frontal gyrus, superior tem- poral gyrus, amygdala and putamen; tyrosine hydroxylase immunohistochemistry of putamen; and microgliosis in substantia nigra and basal nucleus of Meynert. We will record clinical phenotypes (as for PSP, but also dementia and/or Parkinsonism), pathological phenotypes (brainstem, transitional, or diffuse LBD; pure LBD vs. mixed LBD) as well as Lewy body counts in 5 cortical areas and the amygdala. We will estimate latent trait variables underly- ing the semiquantitative scores of LBs, plaques and tangles as in Aim 1. Aim 4. Assess association of inter- mediate pathologic phenotypes with gene variants from PD GWAS. SNPs will be identified as top hits from the autopsy PD GWAS. We will focus on 2 MAPT SNPS and 23 non-/W>!\P7SNPs that achieved p<1x10'(R). Each SNP will be tested for association with 9 intermediate phenotypes in more than 700 LBD cases. Ultimately, ge- netic and phenotypic data on a large number of PSP and LBD brains will not only provide mechanistic insight, but also be a resource for Udall Center collaborators and for others.